A 38 yo male from a kindred with familial hyperalphalipoproteinemia was diabetic and normally ingested a diet extremely high in fat (55% calories) consisting of fried chicken wings and rum. Baseline lipids included TC=278, TG=62 and HDL levels ranging from 225-250mg/dl. The effects of dietary fat and alcohol were investigated in the proband using a typical American diet (35% fat), high fat (55% fat) and high fat with alcohol (40%) diets. On the latter diet the proband was given rum daily with incremental increases of 3,6,9,12, and 18oz every 2 weeks. TC progressively increased on the 3 diets from 228mg/dl to 350mg/dl. Fasting TG averaged 110,100, and 49mg/dl on the 3 diets respectively. On the fat/alcohol diet lipoprotein lipase activity was increased 2 fold compared to controls. ApoB decreased from 86 to 63mg/dl. ApoA-I increased to a peak of 536 mg/dl (nl 120+/-12 mg/dl) with no change in the apoA-II levels. HDL-C increased from 99 to 278mg/dl. The metabolic basis of the increased HDL in the proband was evaluated using 125I-apoA-I and 131I-apoA-II kinetics over 14d on both the American and high fat diet with 18oz of rum. On the American diet the apoA-I FCR was similar to controls (0.246 vs 0.225d-1), however the PR of the proband was increased 23.2 vs 10.5mg/d gm of controls. The FCR and PR of apoA-II were similar to controls. On the high fat diet with alcohol the FCR of apoA-I and apoA-II did not change while the PR of apoA-I increased dramatically to 41.1mg/d gm with no change in the apoA-II PR. The percent of LpA-I particles in HDL increased to 70% with alcohol. Thus, inncreased HDL was due to a dramatic selective increased synthesis of apoA-I. The addition of alcohol to the high fat diet increased LpA-I particles synthesis and stimulated lipase activity leading to further increased HDL and decreased TG levels.